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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
2007-8-16
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pubmed:abstractText |
Four 2-substituted Tet-AMPA [Tet = tetrazolyl, AMPA = 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] analogues were characterized functionally at the homomeric AMPA receptors GluR1i, GluR2Qi, GluR3i, and GluR4i in a Fluo-4/Ca2+ assay. Whereas 2-Et-Tet-AMPA, 2-Pr-Tet-AMPA, and 2-iPr-Tet-AMPA were nonselective GluR agonists, 2-Bn-Tet-AMPA exhibited a 40-fold higher potency at GluR4i than at GluR1i. Examination of homology models of the S1-S2 domains of GluR1 and GluR4 containing 2-Bn-Tet-AMPA suggested four nonconserved residues in a region adjacent to the orthosteric site as possible determinants of the GluR4i/GluR1i selectivity. In a mutagenesis study, doubly mutating M686V/I687A in GluR1i in combination with either D399S or E683A increased both the potency and the maximal response of 2-Bn-Tet-AMPA at this receptor to levels similar to those elicited by the agonist at GluR4i. The dependence of the novel selectivity profile of 2-Bn-Tet-AMPA upon residues located outside of the orthosteric site underlines the potential for developing GluR subtype selective ligands by designing compounds with substituents that protrude beyond the (S)-Glu binding pocket.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-amino-3-(3-hydroxy-5-(2-benzyl-2H-...,
http://linkedlifedata.com/resource/pubmed/chemical/Aniline Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Fluo 4,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorescent Dyes,
http://linkedlifedata.com/resource/pubmed/chemical/Isoxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Propionic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, AMPA,
http://linkedlifedata.com/resource/pubmed/chemical/Tetrazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Xanthenes,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-Amino-3-hydroxy-5-methyl-4-iso...,
http://linkedlifedata.com/resource/pubmed/chemical/glutamate receptor ionotropic...,
http://linkedlifedata.com/resource/pubmed/chemical/glutamate receptor ionotropic...,
http://linkedlifedata.com/resource/pubmed/chemical/glutamate receptor ionotropic...,
http://linkedlifedata.com/resource/pubmed/chemical/glutamate receptor ionotropic...
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
23
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4177-85
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pubmed:meshHeading |
pubmed-meshheading:17672447-Aniline Compounds,
pubmed-meshheading:17672447-Animals,
pubmed-meshheading:17672447-Binding Sites,
pubmed-meshheading:17672447-Cell Line,
pubmed-meshheading:17672447-Female,
pubmed-meshheading:17672447-Fluorescent Dyes,
pubmed-meshheading:17672447-Humans,
pubmed-meshheading:17672447-Isoxazoles,
pubmed-meshheading:17672447-Models, Molecular,
pubmed-meshheading:17672447-Mutation,
pubmed-meshheading:17672447-Oocytes,
pubmed-meshheading:17672447-Patch-Clamp Techniques,
pubmed-meshheading:17672447-Propionic Acids,
pubmed-meshheading:17672447-Rats,
pubmed-meshheading:17672447-Receptors, AMPA,
pubmed-meshheading:17672447-Sequence Homology, Amino Acid,
pubmed-meshheading:17672447-Stereoisomerism,
pubmed-meshheading:17672447-Structure-Activity Relationship,
pubmed-meshheading:17672447-Tetrazoles,
pubmed-meshheading:17672447-Thermodynamics,
pubmed-meshheading:17672447-Xanthenes,
pubmed-meshheading:17672447-Xenopus,
pubmed-meshheading:17672447-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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pubmed:year |
2007
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pubmed:articleTitle |
Functional characterization of Tet-AMPA [tetrazolyl-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)propionic acid] analogues at ionotropic glutamate receptors GluR1-GluR4. The molecular basis for the functional selectivity profile of 2-Bn-Tet-AMPA.
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pubmed:affiliation |
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. aaj@farma.ku.dk
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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